Transcript Document

The Role and Value of Nonclinical PK,
PD and Immunogenicity Assessments
in a Comparability Strategy
Paul C. Francis, Ph.D.
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Outline
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General Strategy for Comparability Assessment
Considerations for PK/PD Comparability Study
Study Objectives
Case Study 1
Case Study 2
Regulatory Feedback
Summary / Conclusions
General Strategy for a
Comparability Assessment
• Comparability strategy for two Mabs (in Phase 2) derived
from different cell lines included:
– Physical-chemical comparisons of the materials
– In vitro biological assays
– Concurrent in vivo comparison of biological effects
• Strategy is consistent with regulatory guidelines
– EMEA Guideline on Comparability of Biotechnology-Derived
Medicinal Products After a Change in the Manufacturing
Process, Non-Clinical and Clinical Issues – July 2007
– FDA Guidance Concerning Demonstration of Compatibility of
Human Biological Products, Including Therapeutic
Biotechnology-derived Products – April 1996
Prerequisites for Using a PK/PD Study to
Assess Comparability
• Molecule should only produce PD-related effects at
maximum dose tested in a repeat-dose study
– No off-target-related toxicity at doses up to 10X the maximum
clinical dose
• Robust in vivo PD marker needs to be available
• PK profile should be well characterized in species to be
tested
• Immunogenicity assay for anti-drug antibodies should be
available
Study Objectives
• Directly compare the pharmacodynamic response (and
recovery) and pharmacokinetic profile of a Mab derived
from two different cell lines
– Ideally, test a dose that produces a robust,
sub-maximal PD effect
• Evaluate these parameters in cynomolgus monkeys
administered two weekly doses followed by a non-dosing
recovery period
• Minimize animal usage and limit the overall study
complexity and duration, resource needs, and costs
Case Study 1
Toxicology Profile for Mab1
• Only binds to target in humans, NHP’s, and rabbits
• Repeat-dose studies in Cynomolgus monkeys
– 6-Week study: IV dosing (0.1, 1.0, 30 mg/kg) every 2 wk
followed by 4-mo recovery period
– 6-Month study: IV or SC dosing (0.1, 1.0, 30 mg/kg) every 2 wk
followed by 4-mo recovery period
– Results were similar between 6-wk and 6-mo studies
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No treatment-related adverse effects at any dose level
Reduced leukocyte counts in peripheral blood (expected PD effect)
PD-related histopathology changes in lymphoid tissues in 6-mo study
Full recovery of PD changes in low-dose group, partial recovery
at mid and high doses after 4 mo
• Serum t1/2 was dose-related and ranged from 7.5 to 27 days
• Negative for ADA
• NOAEL = 30 mg/kg in both studies
Case Study 1
Study Design Elements
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Species: Cynomolgus monkey, male and female
Test Articles: derived from NS0 cells
derived from CHO cells
Route: Subcutaneous injection
No. Animals: 3/sex/group
Dose Level: 0.3 mg/kg (no control group)
Dosing Duration: 1 week (dose on Days 1 and 8)
Recovery Period: 12 weeks
Endpoints:
Clinical observations
Body weight and food consumption
Serum pharmacokinetics (PK) profile
Pharmacodynamic (PD) endpoint
Immunogenicity (ADA titers)
Serum Mab1 Concentration (g/mL
Serum Concentrations of Mab1 in Cynomolgus
Monkeys Following Subcutaneous
Administration of 0.3 mg/kg on Days 1 and 8
100
NS0
CHO
10
1
D8
0.1
0.01
0.001
0
336
672
1008
1344
Time (hr)
1680
2016
Immunogenicity of Mab1
• 11 out of 12 animals were negative for ADA
• 1 animal administered CHO-derived Mab
showed a low titer of ADA on Day 91, but there
was no impact on the PK profile or PD
response in this animal
• Conclusion: No difference in the
immunogenicity of NS0- or CHO-derived Mab1
Mean (±SD) PK Parameters of Mab1 in
Cynomolgus Monkeys Following Subcutaneous
Administration of 0.3 mg/kg on Days 1 and 8
Parameter
NS0
CHO
AUC0-∞ (g-hr/mL)
3122 ± 1054
2575 ± 352
Cmax (g/mL)
5.7 ± 3.9
4.1 ± 0.3
t1/2 (hr)
371 ± 91
239 ± 102
Group Mean (±SD) of PD Marker Normalized to
Baseline in Cynomolgus Monkeys Given
0.3 mg/kg by SC Injection on Days 1 and 8
180
NS0
CHO
PD Marker (% of Baseline)
160
140
120
100
80
D1
D8
60
40
20
0
Baseline 7
14
21
28
42
Study Day
56
70
84
91
Case Study 2
Toxicology Profile for Mab2
• Only binds to target in humans and NHP’s
• 4-Week repeat-dose study in Cynomolgus monkeys
– IV dosing (1.0, 30, 100 mg/kg) every week followed by
6-mo recovery period
– Summary of results
• No treatment-related adverse effects at any dose level
• Reduced leukocyte counts in peripheral blood at all doses
(expected PD effect)
• Full recovery of PD changes by 20 weeks post dosing
• PD-related histopathology changes in lymphoid tissues
• Serum t1/2 was dose-related; ranged from 2.1 to 7.3 days
• All animals positive for ADA
• NOAEL = 100 mg/kg
Case Study 2
Study Design Elements
• Species: Cynomolgus monkey, male and female
• Test Articles: derived from DG44 CHO cells (Group 1)
derived from GS CHO cells (Group 2)
• Route: Intravenous injection
• No. Animals: 3/sex/group
• Dose Level: 1.0 mg/kg (no control group)
• Dosing Duration: 1 week (dose on Days 1 and 8)
• Recovery Period: 8 weeks
• Endpoints:
Clinical observations
Body weight and food consumption
Serum pharmacokinetics (PK) profile
Pharmacodynamic (PD) endpoint
Immunogenicity (ADA titers)
Serum Mab2 Concentration (ng/mL
Pharmacokinetics of Mab2 from DG44 CHO and GS CHO
Cell Lines Following Intravenous Administration of
1.0 mg/kg to Cynomolgus Monkeys on Days 1 and 8
100000
10000
1000
D1
D8
100
DG44 CHO
GS CHO
10
1
0
100
200
300
Time (hr)
400
500
600
Immunogenicity of Mab2
• 12 out of 12 animals were positive for ADA
at all time points sampled (Weeks 1, 4, and 8)
• Conclusion: No difference in the
immunogenicity of DG44 CHO- or GS CHOderived Mab2
Mean (±SD) PK Parameters of Mab2 in Cynomolgus
Monkeys Following Intravenous Administration
of 1.0 mg/kg on Days 1 and 8
Parameter
DG44 CHO
GS CHO
AUC0-∞ (g-hr/mL)
845.0 ± 307.9
691.8 ± 318.2
Cmax (g/mL)
17.1 ± 5.1
14.8 ± 4.8
t1/2 (hr)
38.9 ± 10.1
19.7 ± 11.9
PD Marker (% of Baseline)
Group Mean (±SD) of Biomarker Normalized to
Baseline in Cynomolgus Monkeys Given
1.0 mg/kg by IV Injection on Days 1 and 8
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
-10
1
DG44 CHO
GS CHO
D8
8
15
22
29
36
43
Study Day
50
57
64
71
Regulatory Feedback
• Case Study 1
– Preliminary results from PK/PD study and CM&C comparability
data submitted to FDA as part of an IND amendment
– Currently under review by FDA
• Case Study 2
– Preliminary results from PK/PD study and proposed CM&C
comparability protocol submitted to FDA as pre-read for a
Type C meeting
– FDA indicated that they will make their assessment after the final
PK/PD study report and CM&C comparability data have been
submitted
– Comments at the Type C meeting suggested that results from the
PK/PD study would be accepted as supporting comparability as
long as the preliminary data submitted in the Briefing Document
was corroborated in the final study report
Conclusions
• An acceptable comparability strategy for Mabs derived from
different cell lines should include a CM&C assessment, in
vitro assays, and an in vivo evaluation of biological effects
and PK
• If the Mab only produces any PD-related toxicity in a
repeat-dose study, then limiting the primary parameters in
the in vivo study to PK and PD may be acceptable
• ADA titer can be helpful for interpreting the PK/PD results
• Results may influence decision on whether a clinical
comparability study is needed
Acknowledgements
Jennifer Martin
John Kamerud
Wendy Komocsar
Dan Wierda
Holly Smith
Jamie Blackbourne
Discussion Questions
Discussion Questions
• Is immunogenicity an important comparability
parameter in a nonclinical study?
• If a Mab produces non-PD-related toxicity, is it
essential to include that endpoint in a
comparability assessment?
• Do in vivo comparability studies in non-human
primates need to be statistically rigorous?